Patient motion is an ever-present potential cause of artifacts that can limit the accuracy of diagnostic imaging. The problem is especially significant for imaging modalities such as SPECT and PET, which require the patient to remain motionless for protracted periods of time, and multimodality imaging where patient alignment between the modalities is essential. Our hypothesis is that integrating into iterative reconstruction combined information from a visual-tracking-system (VTS) and the imaging modalities themselves will result in a robust motion-correction strategy. By VTS we mean a computational system that processes stereo-images of retro-reflective markers on the patient surface to provide a source of motion information that is independent of the clinical imaging system(s). The types of patient motion for which compensation will be investigated for cardiac perfusion SPECT imaging with this combined approach are rigid-body motion (RBM), non-rigid-body motion (non-RBM), respiratory motion (RM), cardiac upward creep (which is caused by changes in RM), and motion between sequential multi-modality imaging studies. Note we correct body-motion and RM differently, thus we differentiate between them as part of motion estimation. In this competitive renewal we propose to extend our current VTS to include application with multimodality imaging, emission data-consistency, and finite-element-modeling (FEM) based correction of non-RBM. MRI of volunteers will be employed to establish the relationship between external-marker motion and the motion of the heart within the body. MRI will also provide high-resolution anatomy of the chest at different motion states in combination with measured-marker motion to guide the creation of realistic SPECT simulations for refinement of algorithms. Initial clinical testing will make use of repeat-rest cardiac-SPECT studies in patient-volunteers where the first rest imaging study serves as the standard for judging the success of correction of the second study during which the patients intentionally move. The ultimate assessment of the success of our hypothesis will be physician-observer ROC studies comparing the detection accuracy of coronary artery disease (CAD) with and without motion compensation for patients undergoing SPECT perfusion imaging with the results of cardiac catheterization serving as the gold standard. We believe the significance of our proposed investigations lies not only in the potential to improve diagnostic accuracy through motion-correction of both cardiac and non-cardiac SPECT, PET, and multimodality imaging but also in affording a better understanding of patient motion during imaging.